HBV-driven expansion of CXCR6+-exhausted T cells and CXCL16+ macrophage interaction: Implications for immunotherapy in HCC.

Hepatitis B virus (HBV) may alter immunotherapy responsiveness in HBV-positive hepatocellular carcinoma (HCC) patients. However, the underlying immune mechanisms remain unclear. To characterize the immune determinants underlying the enhanced immunotherapy response observed in HBV+ HCC patients, we comprehensively analyzed 528 HCC patients who received immunotherapy, encompassing diverse hepatitis infections. We performed an analysis incorporating single-cell RNA sequencing, spatial transcriptomics, and tissue microarray validation to map the tumor immune landscape. An adoptive T cell transfer combined with anti-programmed death-1 (PD-1) therapy in a syngeneic HCC mouse model was performed to validate key findings. HBV+ HCC patients exhibited superior responses to immunotherapy and prolonged overall survival. Remarkably, HBV+ HCC patients harbored an elevated proportion of exhausted CD8+ T cells, and these cells concurrently exhibited enhanced immune activity and cytotoxic potential. Our study spotlighted a novel subset of exhausted CD8+ T cells, termed PD-1+ CXCR6+ CD8+ T cells. In untreated cases, high levels of PD-1+ CXCR6+ CD8+ T cells correlated with poor prognosis. In contrast, among patients receiving immunotherapy, their enrichment was associated with markedly better outcomes. In vivo, adoptive transfer of CXCR6+ T cells markedly augmented the antitumor efficacy of anti-PD-1 therapy. Moreover, PD-1+ CXCR6+ CD8+ T cells demonstrated a prominent interaction with CXCL16+ macrophages in HBV+ HCC. Taken together, we identified a novel exhausted T cell subset, PD-1+ CXCR6+ CD8+ T cells, that are enriched in HBV+ HCC patients and maintained by CXCL16+ macrophages. The enrichment of PD-1+ CXCR6+ CD8+ T cells and their interaction with CXCL16+ macrophages may contribute to the enhanced immunotherapy response observed in HBV+ HCC.